Local regulation of cytotoxic T cell function in the tumor stroma

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The applicant started training in pediatric and experimental surgery in Germany. Through questions related to leukocyte migration in surgical disease states, such as shock and ischemia-reperfusion, he arrived at a basic science perspective on disease. He has come to the U.S. to start post-doctoral work in Immunology and has since then committed himself to basic research in this field. His general interest is how leukocyte function is enabled through migration and cellular interaction. Specifically, he studies T cell function through direct in vivo visualization using intravital microscopy approaches. His long-term career goal is to establish himself as an independent investigator at a basic research institution with a strong interest in immunology. Cytotoxic T lymphocytes (CTL) critically contribute to anti-tumor immunity through contact-dependent cytotoxicity. The single-cell kinetics and efficiency of direct killing of tumor cells by CTL in vivo are not known and it is unclear to what extent cytotoxicity is directly conferred upon either tumor cells or constituents of the tumor stroma. This project will address these open questions by direct dynamic visualization of CTL-tumor cell interaction and tumor cell death in vivo. Effector T cells are controlled by peripheral tolerance mechanisms, including the action of regulatory T cells (Treg). It is not known by what mechanisms and at what levels Treg control immune responses. This research project will investigate the hypothesis that Treg suppress CTL effector function against tumors in a temporally and spatially restricted manner. Multiphoton intravital microscopy generates real-time recordings of migrating cells at subcellular resolution and will be used to address the following specific aims: 1.) To characterize the spatial, behavioral, and functional relationship of CTL and tumor cells in vivo 2.) To examine if and how Treg control CTL homeostasis, behavior and function in tumors. The proposed experiments will generate a mechanism-oriented outline of CTL function in peripheral tissues. The aim of this study is to increase our general understanding of how immune responses are regulated. Such knowledge is prerequisite for the rational design of therapeutic regimen designed to either enhance desired immune responses, e.g. against tumors, or suppress undesired responses, such as in autoimmune diseases.